A study documenting for the first time the role of the liver as a target of the metabolic effects of endocannabinoids in diet-induced obesity has now been published. In this study we found that endogenous cannabinoids acting at CB1 receptors (CB1) stimulate appetite, and CB1 antagonists show promise in the treatment of obesity. CB1 knockout (CB1-/-) mice are resistant to diet-induced obesity even though their caloric intake is similar to wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. We investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB1 in mice increases the hepatic gene expression of the lipogenic transcription factor sterol response element-binding protein-1c (SREBP1c) and its targets acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FAS). Treatment with a CB1 agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB1. High fat diet increases hepatic levels of the endocannabinoid anandamide, CB1 density, and basal rates of fatty acid synthesis, and the latter is reduced by CB1 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP1c and FAS expression are similarly affected by CB1 ligands. We conclude that anandamide acting at hepatic CB1 contributes to diet-induced obesity, and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation. Endocannabinoids acting at CB1 cannabinoid receptors (CB1) increase appetite. In view of the predominant presynaptic localization of CB1 in the brain, we tested the hypothesis that the orexigenic effect of endocannabinoids involves inhibition of the release of a tonically active anorexigenic mediator, such as the peptide product of the cocaine and amphetamine-related transcript (CART). The CB1 antagonist rimonabant inhibited food intake in food-restricted wild-type mice, but not in their CART-deficient littermates. Mice deficient in fatty acid amide hydrolase (FAAH), the enzyme responsible for the in vivo metabolism of the endocannabinoid anandamide, have reduced levels of CART immunoreactive nerve fibers and terminals in several brain regions implicated in appetite control, including the arcuate, dorsomedial and periventricular nuclei of the hypothalamus, the amygdala, the bed nucleus of the stria terminalis and the nucleus accumbens, and treatment of FAAH-/- mice with rimonabant, 3 mg/kg/day for 7 days, increased CART levels toward those seen in FAAH+/+ wild-type controls. In contrast, no difference in the density of CART immunoreactive fibers was observed in the median eminence and the paraventricular nucleus of FAAH+/+ and FAAH-/- mice. Acute treatment of wild-type mice with the cannabinoid agonist HU-210 resulted in elevated CART levels in the dorsomedial nucleus and the shell portion of the nucleus accumbens. These observations are compatible with CART being a downstream mediator of the CB1-mediated orexigenic effect of endogenous anandamide We have continued a phase I/II clinical trial testing the safety and efficacy of the CB1 receptor antagonist rimonabant in reducing the desire to drink among heavy drinkers. The study, approved by the institional IRB, will include 40 subjects on a double-blind, placebo controlled basis. Subjects take 20 mg rimonabant daily for two weeks, following which they participate in a test where they have the option to drink 8 glasses of liquor over a 4 hour period, followed by a neuropsychiatric assessment for their subjective desire and response to drinking as well as a neuroendocrine evaluation. The study is currently in progress, we have just enrolled subject #24 and are aiming to complete the study by late next spring. If found effective, rimonabant may become only the fourth drug to be used for the treatment of alcoholics in the United States (after disulfiram, naltrexone and acamprosate).